The activity of some voltage-gated calcium channels (VGCCs) can be inhibited by specific G protein β subunits. Conversely,
in the case of N-type VGCCs, protein kinase C can relieve Gβ-dependent inhibition by phosphorylating at least one specific site on the calcium channel. A recent publication describes
a newly identified method of intracellular regulation of specific VGCCs. Wu et al. have uncovered that VGCC activity can be
regulated by phosphatidylinositol-4′,5′-bisphosphate (PIP2 ). Whereas PIP2 is important for maintaining the activity (open state) of Cav2.1 (N-type) and Cav2.2 (P/Q-type) channels, the enzymatic breakdown of PIP2 leads to the inactivation of these channels. Additionally, PIP2 can cause changes in voltage-dependent activation of Cav2.2 (P/Q-type) channels that make it more difficult for these channels to open (from the closed state). Furthermore, protein
kinase A activity can circumvent PIP2-mediated inhibition. Thus, the PIP2-mediated regulation of VGCCs is tightly controlled by the functions of kinases (and phosphatases), as well as phospholipases.
Wu et al. stress that because PIP2 can be found at synapses, PIP2-dependent control of VGCCs “could have profound consequences on synaptic transmission and plasticity.”

François Mach

Toward a Role for Statins in Immunomodulation

The family of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, collectively known as statins, is used clinically
to reduce cholesterol levels in patients. Recent reports suggest that not only would statin therapy be beneficial for at-risk
(genetically predisposed) people without symptoms of hypercholesterolemia, but that statins may have beneficial, pleiotropic
effects in the treatment of autoimmune diseases. Youssef et al. have described how an HMG-CoA inhibitor, atorvastatin, might
ameliorate experimental autoimmune encephalomyelitis (EAE), the mouse model for human multiple sclerosis. The possible clinical
use of statins as anti-inflammatory drugs has also been demonstrated in other published reports. These provocative results
suggest a role for statins in relieving autoimmune diseases such as multiple sclerosis.

Sheila A. Stewart

Multiple Levels of Telomerase Regulation

Normally, cell division leads to shortening of telomeres, the nucleoprotein complexes located at the ends of linear chromosomes.
When telomeres reach a critically short length, cells cease to divide. However, immortal tumor cells display stable telomere
lengths and are able to maintain their proliferative state. Wong and colleagues have found that telomerase is sequestered
by nucleoli during certain stages of the cell cycle, decreasing the likelihood of telomerase access to chromatin until the
late S phase. Additionally, they demonstrate that ionizing radiation tends to keep telomerase sequestered in nucleoli, whereas
cell transformation leads to telomerase translocation into the nucleoplasm, where, presumably, it can catalyze the lengthening
of telomeres at appropriate and inappropriate sites. The sequestration of telomerase thus imposes a newly identified level
of regulation on telomerase activity, implicating telomerase localization as a potentially useful target for pharmacotherapy.

Reviews

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Íbrahim Halil Kavaklı and

Aziz Sancar

Circadian Photoreception in Humans and Mice

Circadian rhythms allow organisms to optimize particular behaviors with regard to the time of day. The molecular mechanisms
that account for the nightlife of mice, and the working day of humans, rest on light-dependent oscillations in the expression
of specific proteins. Chief among these are the cryptochromes, proteins that absorb blue light and appear to act as photoreceptors
in the circadian rhythms of humans and mice, as well as in plants, where cryptochromes were first discovered. Research into
the brain’s clockwork has recently received new impetus, based on an appreciation that the circadian rhythm is germane not
only to disturbances of mood and sleep cycles, but also to pharmacological interventions into disease states such as cancer.

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Hiroshi Hosoda,

Masayasu Kojima,

and Kenji Kangawa

Ghrelin and the Regulation of Food Intake and Energy Balance

By age thirty-five, one in four Americans is obese. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor,
is secreted by the stomach and stimulates food intake. Ghrelin accomplishes this by facilitating growth hormone secretion
and by transducing signals to hypothalamic regulatory nuclei that control energy homeostasis. Hosoda and colleagues review
what is known about the molecular mechanisms by which ghrelin regulates hunger, satiety, and obesity. Understanding how ghrelin
regulates the sensation or perception of hunger may yield promising future therapies for appetite control and overcoming anorexic
behavior.